Researchers at Dana-Farber Cancer Institute, Harvard Medical School (HMS), and the Broad Institute of MIT and Harvard, have linked a gene mutation signature that is indicative of DNA damage, with high red meat consumption and increased cancer-related mortality in patients with colorectal cancer (CRC). The results, the scientists suggest, could feasibly lead to the development of new CRC risk or diagnostic biomarkers, and point to therapeutic opportunities.

The team, headed by Marios Giannakis, MD, PhD, an assistant professor of medicine at HMS and a physician at Dana-Farber Cancer Institute, carried out whole-exome sequencing (WES) of DNA from matched normal and colorectal tumor tissue samples from hundreds of patients with colorectal cancer who had participated in one of three nationwide prospective cohort studies. The results identified, for the first time, “… an alkylating mutational signature in colon cells and linked it to red meat consumption and cancer driver mutations,” Giannakis said. “These findings suggest that red meat consumption may cause alkylating damage that leads to cancer-causing mutations in KRAS and PIK3CA, thereby promoting colorectal cancer development. Our data further support red meat intake as a risk factor for colorectal cancer and also provide opportunities to prevent, detect, and treat this disease.”

Reporting on their studies in Cancer Discovery (“Discovery and features of an alkylating signature in colorectal cancer”) Giannakis and colleagues in the U.S., and in the U.K., concluded, “Together, these results link for the first time a colorectal mutational signature to a component of diet, and further implicate the role of red meat in CRC initiation and progression.”

“We have known for some time that consumption of processed meat and red meat is a risk factor for colorectal cancer,” Giannakis explained. The International Agency for Research on Cancer declared back in 2015 that processed meat was carcinogenic and that red meat was probably carcinogenic to humans. Experiments in preclinical models have suggested that red meat consumption may promote the formation of carcinogenic compounds in the colon, but a direct molecular link to colorectal cancer development in patients has not been shown. As Giannakis further stated, “What is missing is a demonstration that colorectal cancers from patients have a specific pattern of mutations that can be attributed to red meat. Identifying these molecular changes in colon cells that can cause cancer would not only support the role of red meat in colorectal cancer development but would also provide novel avenues for cancer prevention and treatment.”

To identify genetic changes associated with red meat intake, the researchers carried out whole-exome sequencing on matched primary, untreated tumor-normal sample pairs, from 900 CRC patients who participated in three U.S.-wide prospective studies, the Nurses’ Health Studies I and II (NHS), and the Health Professionals Follow-up Study (HPFS). Each patient had previously provided information on their diet, lifestyle, and other factors over the course of several years prior to their colorectal cancer diagnosis. “To test whether dietary components contributed to the alkylating signature in CRC, we leveraged prospectively collected repeated measurements of meat, poultry, and fish consumption in grams per day in the NHS and HPFS cohorts,” they noted.

The team’s analysis of the DNA sequencing data revealed the presence of several mutational signatures in normal and cancerous colon tissue, including a signature indicative of alkylation, a form of DNA damage. The alkylating signature was significantly associated with prediagnosis intake of processed or unprocessed red meat, but not with prediagnosis intake of poultry or fish, or with other lifestyle factors. “All available red meat variables showed significant positive associations between prediagnosis intakes and alkylating damage in CRCs.” Conversely, red meat consumption was not associated with any of the other mutational signatures identified in the investigators’ study. “In addition, no other CRC mutational process showed a significant association with red meat intake,” the authors pointed out.

And in contrast with the findings for red meat consumption, other dietary variables (fish and chicken intake) and lifestyle factors—including body mass index, alcohol consumption, smoking and physical activity—showed no significant association with the alkylating signature.

Using a predictive model, the researchers identified the KRAS and PIK3CA genes as potential targets of alkylation-induced mutation. Consistent with this prediction, they found that colorectal tumors harboring KRAS G12D, KRAS G13D, or PIK3CA E545K driver mutations, which are commonly observed in colorectal cancer, had greater enrichment of the alkylating signature compared with tumors without these mutations.

There was also a link between the alkylating signature and patient survival, such that patients whose tumors had the highest levels of alkylating damage exhibited a 47% greater risk of colorectal cancer-specific death, compared with patients demonstrating lower levels of damage. “ … the association of the signature with cancer driver mutations—such as KAS and PIK3CA ones—may offer future potential therapeutic opportunities,” the scientists suggested. Interestingly, and in line with prior studies linking red meat consumption with cancer incidence in the distal colon, the investigators’ results indicated that normal and cancerous tissue from the distal colon had significantly higher alkylating damage than tissue from the proximal colon.

They claim that the combined study results provide “… unique evidence supporting the direct impact of dietary behaviors on colorectal carcinogenesis … Our work demonstrated the presence of a novel alkylating mutational signature, which we deconvoluted directly from WES of colorectal tumors,” they commented. Interestingly, they continued, the signature is very similar to a reference COSMIC single base substitution (SBS) signature SBS11, which was originally discovered in patients with prior exposure to the alkylating agent temozolomide, a chemotherapy drug that is used to treat certain brain gliomas.

Giannakis suggests that if physicians could identify individuals who are genetically predisposed to accumulating alkylating damage, these individuals could be counseled to limit their red meat intake as a form of precision prevention. The alkylating mutational signature could also feasibly be used as a biomarker to identify patients at greater risk of developing colorectal cancer, or potentially to detect cancer at an early stage. “Similarly, the association of the signature with cancer driver mutations—such as KRAS and PIK3CA ones—may offer future potential therapeutic opportunities.

And because of its association with patient survival, the alkylating signature may feasibly have relevance as a prognostic biomarker. However, future studies are needed to explore these possibilities, Giannakis noted. But more generally, the team pointed out, “our study exemplifies the potential role of large-scale molecular epidemiologic studies elucidating cancer pathogenesis and guiding prevention efforts through lifestyle modifications, such as dietary interventions.”

One limitation of the study is the potential selection bias of study participants, as tissue specimens could not be retrieved from all incident colorectal cancer cases in the cohort studies. Current studies by Giannakis and his colleagues are exploring the potential role of red meat intake and alkylating damage in diverse groups of patients.

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